Department of Radiation Oncology, University of Colorado Denver and Health Science Center, Aurora, USA.
Int J Radiat Oncol Biol Phys. 2010 Oct 1;78(2):521-6. doi: 10.1016/j.ijrobp.2009.07.1715. Epub 2010 Feb 3.
To determine the maximal tolerated dose of bortezomib with concurrent external beam radiation therapy in patients with incurable solid malignant tumors requiring palliative therapy.
An open label, dose escalation, phase I clinical trial evaluated the safety of three dose levels of bortezomib administered intravenously (1.0 mg/m(2), 1.3 mg/m(2), and 1.6 mg/m(2)/ dose) once weekly with concurrent radiation in patients with histologically confirmed solid tumors and a radiographically appreciable lesion suitable for palliative radiation therapy. All patients received 40 Gy in 16 fractions to the target lesion. Dose-limiting toxicity was the primary endpoint, defined as any grade 4 hematologic toxicity, any grade ≥3 nonhematologic toxicity, or any toxicity requiring treatment to be delayed for ≥2 weeks.
A total of 12 patients were enrolled. Primary sites included prostate (3 patients), head and neck (3 patients), uterus (1 patient), abdomen (1 patient), breast (1 patient), kidney (1 patient), lung (1 patient), and colon (1 patient). The maximum tolerated dose was not realized with a maximum dose of 1.6 mg/m(2). One case of dose-limiting toxicity was appreciated (grade 3 urosepsis) and felt to be unrelated to bortezomib. The most common grade 3 toxicity was lymphopenia (10 patients). Common grade 1 to 2 events included nausea (7 patients), infection without neutropenia (6 patients), diarrhea (5 patients), and fatigue (5 patients).
The combination of palliative external beam radiation with concurrent weekly bortezomib therapy at a dose of 1.6 mg/m(2) is well tolerated in patients with metastatic solid tumors. The maximum tolerated dose of once weekly bortezomib delivered concurrently with radiation therapy is greater than 1.6 mg/m(2).
确定无法治愈的需要姑息治疗的实体恶性肿瘤患者联合使用硼替佐米和外照射放疗的最大耐受剂量。
一项开放性标签、剂量递增的 I 期临床试验评估了三种剂量水平的硼替佐米（1.0mg/m2、1.3mg/m2 和 1.6mg/m2/剂量）静脉给药联合放疗在组织学证实的实体瘤和可进行姑息性放疗的可测量病变患者中的安全性。所有患者均接受 40Gy 16 次分割至靶病变。剂量限制毒性是主要终点，定义为任何 4 级血液学毒性、任何 3 级或更高级别的非血液学毒性或任何需要治疗延迟≥2 周的毒性。
共入组 12 例患者。主要部位包括前列腺（3 例）、头颈部（3 例）、子宫（1 例）、腹部（1 例）、乳腺（1 例）、肾脏（1 例）、肺（1 例）和结肠（1 例）。最大耐受剂量未达到，最高剂量为 1.6mg/m2。1 例患者出现剂量限制毒性（3 级尿脓毒症），认为与硼替佐米无关。最常见的 3 级毒性是淋巴细胞减少症（10 例）。常见的 1 级至 2 级事件包括恶心（7 例）、无中性粒细胞减少的感染（6 例）、腹泻（5 例）和疲劳（5 例）。
在转移性实体瘤患者中，姑息性外照射联合每周硼替佐米治疗（剂量为 1.6mg/m2）具有良好的耐受性。硼替佐米每周一次与放疗同时使用的最大耐受剂量大于 1.6mg/m2。
